Cyclophilin D Knockout Reduced the Development of Cognitive and Social Behavioral Deficits That Result from Perinatal Ketamine Treatment in Male Ppif-/- Mice

dc.contributor.ORCID0000-0002-7762-6453 (Bairuty, DS)
dc.contributor.advisorKroener, Sven
dc.creatorBairuty, Dania S.
dc.date.accessioned2020-07-27T18:34:21Z
dc.date.available2020-07-27T18:34:21Z
dc.date.created2018-05
dc.date.issued2018-05
dc.date.submittedMay 2018
dc.date.updated2020-07-27T18:34:23Z
dc.description.abstractChange in reduction-oxidation (redox) states has been implicated in the pathogenesis of schizophrenia. N-methyl-D-aspartate (NMDA) receptor blockage can reproduce the behavior observed in schizophrenia in healthy human and animal subjects. Perinatal delivery of ketamine, an NMDA receptor antagonist, produces behavioral deficits in adult mice resulting in a range of symptoms seen in schizophrenia. It is worth noting that studies showing the effects of ketamine in rodent models have been performed in males almost exclusively. However, previous studies in female rats have shown that the administration of PCP, another NMDA receptor antagonist, produces symptoms seen in schizophrenia such as reduced social interaction and deficits in attention and recognition memory. Mitochondrial DNA is particularly susceptible to attack by reactive oxygen species related to oxidative stress. Constant damage to mitochondria can give rise to mutations that lead to further mitochondrial dysfunctional, affecting endogenous antioxidant systems. The mitochondrial permeability transition pore (mPTP) plays a crucial role in facilitating apoptotic and necrotic cell death. Opening of the mPTP results in a collapse of membrane potential leading to mitochondrial swelling and breakage of the outer membrane, releasing apoptotic proteins. The mPTP is believed to be comprised of the adenine nucleotide translocase, a voltage-dependent anion channel, and cyclophilin D (CypD). CypD, a product of the Ppif gene, inhabits the mitochondrial matrix and interacts with the inner mitochondrial membrane during opening of the mPTP. Oxidative stress triggers CypD to relocate to the inner membrane, and this event seems to play a key role in the opening of the mPTP. The use of CypD inhibitors has shown to protect mitochondria from harmful reactive oxygen species. Here, we examined whether Ppif null mice (Ppif-/-) deficient in cyclophilin D could prevent the developmental effects of schizophrenia. On postnatal days (PND) 7, 9, and 11, wild-type (WT) and Ppif-/- mice groups were treated with subanesthetic doses of either ketamine (30mg/kg) or saline, creating four different test groups. Unlike the majority of previous studies using the ketamine model of schizophrenia, both male and female mice were used in this study to explore the behavioral differences between the two sexes. Adult mice (PND 70-140) underwent multiple behavioral assessments to evaluate behavioral changes. Interestingly, there were large behavioral disparities between male and female animals. Male ketamine-treated animals showed deficits in novel object recognition, deficits in social interaction, and cognitive flexibility that were strongly reduced in the knockout model. No significant behavioral differences were observed in female animals regardless of treatment. These results indicate that the lack of cyclophilin D protects the male animals from ketamine-induced schizophrenia-like deficits, suggesting that oxidative strain on cells is a key contributor in the progression of the behavioral deficits observed. These results also create further questions that require more in-depth studies in female animals to investigate the behavioral disparities.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10735.1/8739
dc.language.isoen
dc.rights©2018 Dania S. Bairuty. All rights reserved.
dc.subjectPeptidylprolyl isomerase
dc.subjectSchizophrenia
dc.subjectMethylphenyltetrahydropyridine
dc.subjectOxidative stress
dc.subjectActive oxygen
dc.subjectRodents as laboratory animals
dc.subjectSocial interaction
dc.titleCyclophilin D Knockout Reduced the Development of Cognitive and Social Behavioral Deficits That Result from Perinatal Ketamine Treatment in Male Ppif-/- Mice
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentBiology - Molecular and Cell Biology
thesis.degree.grantorThe University of Texas at Dallas
thesis.degree.levelMasters
thesis.degree.nameMS

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